Cancer

These two papers published in 2018 review the existing literature and make a strong case for the use of intravenous vitamin C in cancer and sepsis patients. Both articles highlight the fact that IV vitamin C has been shown to be a safe intervention leading to improvement of symptoms.

Intravenous vitamin C in the supportive care of cancer patients: a review and rational approach.

Klimant E, Wright H, Rubin D, Seely D, Markman M.

Abstract

This article reviews intravenous vitamin C (IV C) in cancer care and offers a rational approach to enable medical oncologists and integrative practitioners to safely provide IV C combined with oral vitamin C to patients. The use of IV C is a safe supportive intervention to decrease inflammation in the patient and to improve symptoms related to antioxidant deficiency, disease processes, and side effects of standard cancer treatments. A proposed rationale, together with relevant clinical safety considerations for the application of IV C in oncologic supportive care, is provided.

Vitamin C for the treatment of sepsis: The scientific rationale.

Marik PE.

Abstract

Most vertebrates can synthesize vitamin C with synthesis increasing during stress. Humans, however, have lost the ability to synthesize vitamin C. Vitamin C is an important anti-oxidant and an enzyme cofactor for many important biological reactions. Sepsis results in the overwhelming production of reactive oxygen species with widespread endothelial, cellular and mitochondrial injury leading to progressive organ failure. Sepsis is associated with an acute deficiency of vitamin C. In experimental sepsis models, intravenous vitamin C reduces organ injury and improves survival. In addition, emerging evidence suggests that the combination of vitamin C, corticosteroids and thiamine may act synergistically to reverse sepsis induced organ dysfunction. These findings are supported by a recent observational study. Randomized controlled trials are underway to investigate this novel approach to the treatment of sepsis.

Patients with renal (kidney) failure have difficulties processing vitamin C , and the excess ascorbate can accumulate in the body in harmful levels. This research team from Japan studied a molecule derived from vitamin C that can be absorbed more easily: it was found that it also has antitumor properties. This could be an interesting alternative to vitamin C cancer treatment for patients with renal failure.

Abstract

Intravenous administration of high-dose ascorbic acid (AA) has been reported as a treatment for cancer patients. However, cancer patients with renal failure cannot receive this therapy because high-dose AA infusion can have side effects. To solve this problem, we evaluated the antitumor activity of a lipophilic stable AA derivative, 2-O-α-d-glucopyranosyl-6-O-(2-pentylheptanoyl)-l-ascorbic acid (6-bOcta-AA-2G). Intravenous administration of 6-bOcta-AA-2G suppressed tumor growth in colon-26 tumor-bearing mice more strongly than did AA, even at 1/10 of the molar amount of AA. Experiments on the biodistribution and clearance of 6-bOcta-AA-2G and its metabolites in tumor-bearing mice showed that 6-bOcta-AA-2G was hydrolyzed to 6-O-(2-propylpentanoyl)-l-ascorbic acid (6-bOcta-AA) slowly to yield AA, and the results suggested that this characteristic metabolic pattern is responsible for making the antitumor activity of 6-bOcta-AA-2G stronger than that of AA and that the active form of 6-bOcta-AA-2G showing antitumor activity is 6-bOcta-AA. In in vitro experiments, the oxidized form of 6-bOcta-AA as well as 6-bOcta-AA showed significant cytotoxicity, while the oxidized forms of ascorbic acid showed no cytotoxicity at all, suggesting that the antitumor activity mechanism of 6-bOcta-AA-2G is different from that of AA and that the antitumor activity is due to the reduced and oxidized form of 6-bOcta-AA. The findings suggest that 6-bOcta-AA-2G is a potent candidate as an alternative drug to intravenous high-dose AA.

Pancreatic cancer, and in particular pancreatic ductal adenocarcinoma (PDA), has a very poor prognosis – only 6% survive within 5 years of diagnosis. This case report presents a PDA patient with metastasis, with an expected survival of 6 months. He was treated with intravenous vitamin C 2-3 times a week. At the 8-month follow-up, most masses had decreased in size and continued decreasing in subsequent follow-ups. The patient survived 4 years with this regimen, and died of causes indirectly related to PDA, but not associated with PDA progression.

Abstract

Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis and is often discovered at an advanced stage with few therapeutic options. Current conventional regimens for PDA are associated with significant morbidity, decreased quality of life, and a considerable financial burden. As a result, some patients turn to integrative medicine therapies as an alternate option after a diagnosis of PDA. Intravenous pharmacologic ascorbic acid (PAA) is one such treatment. The use of PAA has been passionately debated for many years, but more recent rigorous scientific research has shown that there are significant blood concentration differences when ascorbic acid is given parenterally when compared to oral dosing. This pharmacologic difference appears to be critical for its role in oncology. Here, we report the use of PAA in a patient with poorly differentiated stage IV PDA as an exclusive chemotherapeutic regimen. The patient survived nearly 4 years after diagnosis, with PAA as his sole treatment, and he achieved objective regression of his disease. He died from sepsis and organ failure from a bowel perforation event. This case illustrates the possibility of PAA to effectively control tumor progression and serve as an adjunct to standard of care PDA chemotherapy regimens. Our patient’s experience with PAA should be taken into consideration, along with previous research in cell, animal, and clinical experiments to design future treatment trials.

Acute myeloid leukemia (AML) is a type of cancer that affects the bone marrow, and it may sometimes be treated with decitabine. In this study, AML patients received intravenous low-dose vitamin C and decitabine: they had significantly better overall survival (6 months longer) and a significantly higher remission rate than those who received decitabine alone.

Abstract

BACKGROUND:

Decitabine is widely used in the treatment of acute myeloid leukemia (AML) in elderly patients. Low-dose Vitamin C has also been indicated to induce DNA demethylation at the cellular level. However, little is known whether low-dose Vitamin C has a synergistic effect with decitabine in clinic.

RESULTS:

We found that low-dose Vitamin C and decitabine has a synergistic efficacy on proliferation, apoptosis, TET2 expression and activity, compared to drug-alone treatment in HL60 and NB4 cell lines in vitro. In clinic, feasibility and safety evaluations revealed that patients who received A-DCAG regimen have a higher complete remission (CR) rate than those who received the DCAG regimen (79.92% vs. 44.11%; P = 0.004) after one cycle of chemotherapy. The median overall survival (OS) was better in the A-DCAG group compared with the DCAG group (15.3 months vs. 9.3 months, P = 0.039). Patients with adverse cytogenetics did benefit from CR. There was no clinically significant additional toxicity observed with the addition of IVC.

CONCLUSION:

On the basis of these results, the addition of IVC at low doses to DCAG appeared to improve CR and prolong OS, compared with DCAG, in elderly patients with AML.

In this case report, a patient with renal cancer had his left kidney removed, but cancer metastasized to the left lung. With no conventional therapy options left, he was entered into an intravenous high-dose vitamin C and alpha lipoic acid regimen. The tumor was resolved on PET/CT scan 19 months into the regimen and did not reappear. The patient was healthy as of September 2017, 6 years after the start of treatment.

The Long-Term Survival of a Patient With Stage IV Renal Cell Carcinoma Following an Integrative Treatment Approach Including the Intravenous α-Lipoic Acid/Low-Dose Naltrexone Protocol.

Berkson BM, Calvo Riera F.

Abstract

In this case report, we describe the treatment of a 64-year-old male patient diagnosed with metastatic renal cell carcinoma (RCC) in June of 2008. In spite of a left nephrectomy and the standard oncological protocols, the patient developed a solitary left lung metastasis that continued to grow. He was informed that given his diagnosis and poor response to conventional therapy, any further treatment would, at best, be palliative. The patient arrived at the Integrative Medical Center of New Mexico in August of 2010. He was in very poor health, weak, and cachectic. An integrative program-developed by one of the authors using intravenous (IV) α-lipoic acid, IV vitamin C, low-dose naltrexone, and hydroxycitrate, and a healthy life style program-was initiated. From August 2010 to August 2015, the patient’s RCC with left lung metastasis was followed closely using computed tomography and positron emission tomography/computed tomography imaging. His most recent positron emission tomography scan demonstrated no residual increased glucose uptake in his left lung. After only a few treatments of IV α-lipoic acid and IV vitamin C, his symptoms began to improve, and the patient regained his baseline weight. His energy and outlook improved, and he returned to work. The patient had stable disease with disappearance of the signs and symptoms of stage IV RCC, a full 9 years following diagnosis, with a gentle integrative program, which is essentially free of side effects. As of November 2017 the patient feels well and is working at his full-time job.

This study tested the chemical stability of intravenous ascorbic acid (vitamin C) in the form in which it is administered to patients for the management of cancer. It was found that the compound was still stable 6 hours after preparation – most infusions take place just 2 hours after preparation, which therefore makes them safe for patients.

Abstract

Context • Intravenous ascorbic acid (IVAA) has been used extensively as part of the management plan for cancer patients in various medical clinics throughout the United States. The current research team has evaluated its effectiveness in patients with cancer as part of an ongoing research program. However, no data are available that support the chemical stability of intravenously injectable ascorbic acid (AA) to ensure its safety and efficacy in that patient population. Its clinical use as well as its use in research conducted in US Food and Drug Administration-approved clinical trials require validation of its stability.

Objective • The study intended to evaluate the chemical stability of the compounded IVAA that it prepares.

Design • The research team conducted a stability analysis within a 6-h period, a period longer than the time required for most infusions, which typically take approximately 2 h. The study evaluated the stability of AA intravenous sets, which are compounded solutions for clinical or hospital use. The IVAA was prepared in sterile water, together with magnesium chloride (MgCl) and calcium gluconate (CaGluc) as buffers.

Setting • The study took place at the Marcus Institute of Integrative Health at Thomas Jefferson University (Philadelphia, PA, USA).

Outcome Measures • The study was performed for 2 dosages of an infusion set: 75 g and 100 g of IVAA. Interval testing included pH, particulate matter by light obscuration, and high-performance liquid chromatography assay. Analyses were performed at baseline and at 2-, 4-, and 6-h test intervals.

Results • The results demonstrated that IVAA remained highly stable throughout the 6-h period. It also passed the US Pharmacopeia’s criteria for pH and particulates when used with a 0.2 µ filter. Conclusions • These data suggest that IVAA, when prepared with sterile water, in addition to MgCl and CaGluc, is highly stable and safe to use in patients for up to 6 h after preparation.

This study investigated the effect of adding high-dose intravenous vitamin C to modulated electro-hyperthermia (mEHT), a treatment for cancer. Lung cancer patients received IV high-dose vitamin C in 3 groups: before, after and at the same time as mETH. Later-stage cancer patients were found to have lower plasma levels of vitamin C, and the group who received vitamin C and mETH simultaneously showed higher levels of vitamin C after treatment.

Abstract

Ascorbic acid (AA) infusion and modulated electrohyperthermia (mEHT) are widely used by integrative cancer practitioners for many years. However, there are no safety and pharmacokinetics data in Chinese cancer patients. We carried out a clinical trial to evaluate the safety and pharmacokinetics of those methods in patients with stage III-IV non-small cell lung cancer (NSCLC). Blood ascorbic acid in the fasting state was obtained from 35 NSCLC patients; selecting from them 15 patients with stage III-IV entered the phase I study. They were randomized allocated into 3 groups, and received doses 1.0, 1.2, 1.5g/kg AA infusions. Participants in the first group received intravenous AA (IVAA) when mEHT was finished, in the second group IVAA was administered simultaneously with mEHT and in the third group IVAA was applied first, and followed with mEHT. Pharmacokinetic profiles were obtained when they received solely IVAA and when IVAA in combination with mEHT. The process was applied 3 times a week (every other day, weekend days off) for 4weeks. We found that fasting plasma AA levels were significantly correlated with stage of the disease. Peak concentration of AA was significantly higher in the simultaneous treatments than in other combinations with mEHT or in solely IVAA-managed groups. IVAA synergy with simultaneous mEHT is safe and the concomitant application significantly increases the plasma AA level for NSCLC patients.

This study provides new information on the dynamics of how vitamin C is absorbed, circulates and accumulates in the body for a mouse model: elimination from solid tumors was shown to be slower than from liver and plasma. The formation of blood vessels was reduced and oxygen did not reach the tumors – this happened at optimal levels when high-dose intravenous vitamin C was administered daily.

Pharmacokinetic and anti-cancer properties of high dose ascorbate in solid tumours of ascorbate-dependent mice.

Despite recent evidence for an anti-tumour role for high-dose ascorbate, potential mechanisms of action are still unclear. At mM concentrations that are achieved with high-dose intravenous administration, autoxidation of ascorbate can generate cytotoxic levels of H2O2. Ascorbate is also a required co-factor for the hydroxylases that suppress the transcription factor hypoxia-inducible factor (HIF-1). HIF-1 supports an aggressive tumour phenotype and is associated with poor prognosis, and previous studies have shown that optimizing intracellular ascorbate levels down-regulates HIF-1 activation. In this study we have simultaneously measured ascorbate concentrations and the HIF-1 pathway activity in tumour tissue following high dose ascorbate administration, and have studied tumour growth and physiology. Gulo-/-mice, a model of the human ascorbate dependency condition, were implanted with syngeneic Lewis lung tumours, 1g/kg ascorbate was administered into the peritoneum, and ascorbate concentrations were monitored in plasma, liver and tumours. Ascorbate levels peaked within 30min, and although plasma and liver ascorbate returned to baseline within 16h, tumour levels remained elevated for 48h, possibly reflecting increased stability in the hypoxic tumour environment. The expression of HIF-1 and its target proteins was down-regulated with tumour ascorbate uptake. Elevated tumour ascorbate levels could be maintained with daily administration, and HIF-1 and vascular endothelial growth factor protein levels were reduced in these conditions. Increased tumour ascorbate was associated with slowed tumour growth, reduced tumour microvessel density and decreased hypoxia. Alternate day administration of ascorbate resulted in lower tumour levels and did not consistently decrease HIF-1 pathway activity. Levels of sodium-dependent vitamin C transporters 1 and 2 were not clearly associated with ascorbate accumulation by murine tumour cells in vitro or in vivo. Our results support the suppression of the hypoxic response by ascorbate as a plausible mechanism of action of its anti-tumour activity, and this may be useful in a clinical setting.

In the late 70s, Linus Pauling reported greater long-term survival for cancer patients who were administered oral and intravenous vitamin C – but his paper was dismissed and overlooked following inconclusive clinical trials. Nearly thirty years later, there has been a surge of interest in vitamin C cancer therapy, reflected in an increase of scientific research, including clinical trials. Science Magazine, a prestigious top-tier, high-impact, peer-reviewed academic journal, recently published an article reporting that cancer-inducing gene mutations are selectively killed when exposed to high levels of vitamin C. Just six months ago, Science featured a report discussing recent ascorbate breakthroughs in their News section.

Sardi highlights earlier results of vitamin C therapy, uncovers other works by Pauling that have also been overlooked, and provides a detailed list of research centers and publications – in the past four years, scientists from 13 different countries in 28 universities and clinics have published 37 papers featuring Vitamin C cancer therapy.

High dose ascorbate has been found to selectively target cancer cell lines by inducing production of hydrogen peroxide. This is particularly relevant for Hepatocellular Carcinoma (HHC), where the ability to induce tumor cell death has been compromised. Rouleau et al investigate the mechanism by which ascorbate targets HHC tumor cells, and they subsequently present the case of a patient treated with ascorbate and sorafenib with a significant regression in bony metastasis.